Editorial: Phosphoinositides and their phosphatases: Linking electrical and chemical signals in biological processes

The voltage-sensing phosphatase (VSP) has changed the way we think about both cellular electrical activity and PIPs (phosphatidylinositol phosphates). Originally discovered in 1999 (Chen et al., 1999), these proteins were not recognized as electrically-controlled enzymes until 2005 (Murata et al., 2005). They constitute the first, and so far the only, example of an enzyme linking electrical signals at the plasma membrane to the catalysis of PIPs (Murata et al., 2005), a ubiquitous family of intracellular signaling molecules (Di Paolo and De Camilli, 2006; Balla, 2013). Before the discovery of VSP, there were no known direct links between the two. Textbook examples would represent this connection with arrows, alluding to indirect or “yet-to-be-defined” signaling pathways. Now we know that VSP serves as a direct connection between the electrical nature of the cell and PIPs, lipid second messengers that are critical for cell survival. However, many questions remain unanswered regarding VSP and its electrical regulation of cellular processes. With the discovery of VSP, the membrane potential must now be considered when studying PIP regulators. PIPs are involved in almost all aspects of cell physiology from survival, proliferation, and migration to pre-programed cell death (Di Paolo and De Camilli, 2006; Logothetis et al., 2010; Koch and Holt, 2012; Balla, 2013). For example, PIP concentrations are actively polarized in migrating cells with phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) on the leading edge and phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) on the lagging edge (Leslie et al., 2008). These gradients in the concentration of PIPs are necessary for activation of Rac and Rho leading to cell motion. PIPs are also crucial for cell growth: PI(3,4,5)P3 activates the mTor cascade leading to increased protein, membrane, and nucleic acid production (Dibble and Manning,2013). Many human diseases have been associated with altered homeostasis of PIPs, including cancer, developmental disorders, and Alzheimer\u27s disease (Simpson and Parsons, 2001; McCrea and De Camilli, 2009; Hakim et al., 2012). Though the physiological relevance of VSP is not yet defined, it is still crucial to human health to understand how PIPs are regulated and that now includes VSP. All cells have an asymmetric composition of ions across their plasma membrane, which, combined with selective permeabilities for these ions, results in a difference in the electrical potential across their plasma membrane. This difference, called the membrane potential, constitutes a form of cell signaling and a source of energy, both driving many biological processes. This electrical potential difference powers neuronal excitability as well as more general processes like proliferation, migration, and development (Levin, 2007; Sundelacruz et al., 2009; Yao et al., 2011). Regulation by the membrane potential has long been the sole purview of ion channels and transporters and that has influenced what questions are asked regarding the changing potential. With our new knowledge of VSP, the changing membrane potential can directly signal the cell by modulating mTor and cell growth pathways, leading to abnormal growth or the M-current in sympathetic ganglion, leading to hyperexcitability. The articles in this Special Topic highlight several features of VSP including its unique activation, its similarities to other enzymes and its use as a versatile tool to study other proteins. In the review article by Hobiger and Friedrich (2015, p. 20), the authors compare the structural similarities and differences between the broader family of protein tyrosine phosphatases and one of its newest members, VSP. They suggest a catalytic mechanism based on this comparison. Castle et al. (2015, p. 63) investigate the activation mechanism of VSP by probing the C2 domain, the C-terminal domain of VSP that has been largely unrecognized before the recent crystal structures showed a direct contribution of the C2 residue Y522 into the active site. The work by Mavrantoni et al. (2015, p. 68) explores the techniques that are used to test VSP and address some of their limitations including the need for expensive electrophysiology equipment as well as the limitations of using channels as functional reporters. They take their methods and apply them to a chimera between the Ciona intestinalis VSP and human PTEN and show how the chimera allows for the investigation of PTEN using standard techniques but with the advantage of regulated activation, voltage. Beyond the molecular mechanism underlying VSP activity, Mori et al. (2015, p. 22) review the use of VSP as a relatively simple tool for manipulating PI(4,5)P2 concentrations in cells. They have used VSP to study the PI(4,5)P2 regulation of transient receptor potential canonical channels involved in receptor-operated calcium currents. Along the same lines, Rjasanow et al. (2015, p. 127) use VSP as a tool that gives them precise control over the PI(4,5)P2 concentrations in the membrane. These authors compared the relative PIP affinities between several ion channels. They also point out an important limitation that the channels must already have a known specificity for a particular PIP because VSP does not destroy PIPs in contrast to phospholipase C; instead, it generates multiple PIPs. All together, these articles underscore the features of VSP and expand our understanding of its function and utility. Though VSP remains relatively unknown to many, this nascent field has shown fast initial growth. The unique nature of these enzymes has inspired many to investigate their properties as well as take advantage of them. Many questions remain unanswered regarding VSP such as how the voltage sensor couples to the enzyme and whether the phosphatase domain is brought to the membrane for activation or whether a conformational change within the active site determines activation. We look forward to the studies that will address these and the many other questions that persist in this exciting field

Measurement of the t-channel single top quark production cross section

The D0 collaboration reports direct evidence for electroweak production of single top quarks through the t-channel exchange of a virtual W boson. This is the first analysis to isolate an individual single top quark production channel. We select events containing an isolated electron or muon, missing transverse energy, and two, three or four jets from 2.3 fb^-1 of ppbar collisions at the Fermilab Tevatron Collider. One or two of the jets are identified as containing a b hadron. We combine three multivariate techniques optimized for the t-channel process to measure the t- and s-channel cross sections simultaneously. We measure cross sections of 3.14 +0.94 -0.80 pb for the t-channel and 1.05 +-0.81 pb for the s-channel. The measured t-channel result is found to have a significance of 4.8 standard deviations and is consistent with the standard model prediction.Comment: 7 pages, 6 figure

Measurement of trilinear gauge boson couplings from WW + WZ to lnu jj events in pp-bar collisions at sqrt{s}=1.96 TeV

We present a direct measurement of trilinear gauge boson couplings at gammaWW and ZWW vertices in WW and WZ events produced in pp-bar collisions at sqrt{s}=1.96 TeV. We consider events with one electron or muon, missing transverse energy, and at least two jets. The data were collected using the D0 detector and correspond to 1.1/fb of integrated luminosity. Considering two different relations between the couplings at the gammaWW and ZWW vertices, we measure these couplings at 68% C.L. to be kappa_{gamma}=1.07^{+0.26}_{-0.29}, lambda =0.00^{+0.06}_{-0.06} and g_{1}^{Z}=1.04^{+0.09}_{-0.09} in a scenario respecting SU(2)_L x U(1)_Y gauge symmetry and kappa =1.04^{+0.11}_{-0.11} and lambda=0.00^{+0.06}_{-0.06} in an "equal couplings" scenario.Comment: 14 pages, 7 figures, published in Phys. Rev. D, updated to published versio

Measurement of the W boson mass

We present a measurement of the W boson mass in W -> ev decays using 1 fb^-1 of data collected with the D0 detector during Run II of the Fermilab Tevatron collider. With a sample of 499830 W -> ev candidate events, we measure M_W = 80.401 +- 0.043 GeV. This is the most precise measurement from a single experiment.Comment: As published in PR

Search for the standard model Higgs boson decaying to a bb pair in events with one charged lepton and large missing transverse energy using the full CDF data set

We present a search for the standard model Higgs boson produced in association with a W boson in sqrt(s) = 1.96 TeV p-pbar collision data collected with the CDF II detector at the Tevatron corresponding to an integrated luminosity of 9.45 fb-1. In events consistent with the decay of the Higgs boson to a bottom-quark pair and the W boson to an electron or muon and a neutrino, we set 95% credibility level upper limits on the WH production cross section times the H->bb branching ratio as a function of Higgs boson mass. At a Higgs boson mass of 125 GeV/c2 we observe (expect) a limit of 4.9 (2.8) times the standard model value.Comment: Submitted to Phys. Rev. Lett (v2 contains clarifications suggested by PRL

Double parton interactions in photon+3 jet events in ppbar collisions sqrt{s}=1.96 TeV

We have used a sample of photon+3 jets events collected by the D0 experiment with an integrated luminosity of about 1 fb^-1 to determine the fraction of events with double parton scattering (f_DP) in a single ppbar collision at sqrt{s}=1.96 TeV. The DP fraction and effective cross section (sigma_eff), a process-independent scale parameter related to the parton density inside the nucleon, are measured in three intervals of the second (ordered in pT) jet transverse momentum pT_jet2 within the range 15 < pT_jet2 < 30 GeV. In this range, f_DP varies between 0.23 < f_DP < 0.47, while sigma_eff has the average value sigma_eff_ave = 16.4 +- 0.3(stat) +- 2.3(syst) mb.Comment: 15 pages, 13 figure

Dependence of the ttˉt\bar{t} production cross section on the transverse momentum of the top quark

We present a measurement of the differential cross section for $t\bar{t}$ events produced in $p\bar{p}$ collisions at $\sqrt{s}=1.96$ TeV as a function of the transverse momentum ($p_T$) of the top quark. The selected events contain a high-$p_T$ lepton ($\ell$), four or more jets, and a large imbalance in $p_T$, and correspond to 1 fb${}^{-1}$ of integrated luminosity recorded with the D0 detector. Each event must have at least one candidate for a $b$ jet. Objects in the event are associated through a constrained kinematic fit to the $t\bar{t}\to WbW\bar{b} \to \ell\nu b q\bar{q}'\bar{b}$ process. Results from next-to-leading-order perturbative QCD calculations agree with the measured differential cross section. Comparisons are also provided to predictions from Monte Carlo event generators using QCD calculations at different levels of precision.Comment: 8 pages, 6 figures, 4 tables, updated to reflect the published versio

Search for the standard model Higgs boson decaying to a bbˉb\bar{b} pair in events with no charged leptons and large missing transverse energy using the full CDF data set

We report on a search for the standard model Higgs boson produced in association with a vector boson in the full data set of proton-antiproton collisions at $\sqrt{s} = 1.96$ TeV recorded by the CDF II detector at the Tevatron, corresponding to an integrated luminosity of 9.45 fb$^{-1}$. We consider events having no identified charged lepton, a transverse energy imbalance, and two or three jets, of which at least one is consistent with originating from the decay of a $b$ quark. We place 95% credibility level upper limits on the production cross section times standard model branching fraction for several mass hypotheses between 90 and $150 \mathrm{GeV}/c^2$. For a Higgs boson mass of $125 \mathrm{GeV}/c^2$, the observed (expected) limit is 6.7 (3.6) times the standard model prediction.Comment: Accepted by Phys. Rev. Let